The present invention relates to the field of linking groups or activators that are useful in the solid-phase preparation of single compounds and libraries, as well as methods that employ such linking groups and activators. The present invention also relates generally to the use of activated supports and their use in organic solution phase chemistry and as derivatizing agents to aid in chromatography.
Solid phase synthesis has attracted considerable attention from the scientific community, and in particular, the pharmaceutical and agricultural research communities in an effort to speed up the discovery of new biologically active compounds. Critical to the solid phase synthesis of such compounds are the means to attach (and subsequently remove) the compounds from a support. The most frequently used linkers are acid-labile and photo-labile linkers which typically result in the cleaved product having a residual functional group (e.g., carboxylic acid, amide, amine or hydroxy group). Recently, the term “traceless linker” has been used to describe a strategy of releasing compounds from a solid support with little or no trace of the original point of attachment. See James, Tetrahedron Lett., 1999, 55, 4855; Andres, et al., Curr. Opin. Chem. Biol., 1998, 2, 353; Reitz, Curr. Opin. Drug Discovery Dev., 1999; 2, 358; and Zaragoza, Angew. Chem., Int. Ed. 2000, 39, 2077.
What is needed in the art are polymer support-linker species that activate certain molecules toward other transformations that would be useful in the preparation of single compounds or compound libraries, and that can also act as traceless linkers.
NAFION™ (Dupont, Wilmington, Del.) is a perfluororesinsulfonic acid that could, in principle be used as a traceless linker in solid-phase organic synthesis. However, the inability to utilize NAFION™ resin in high yields and conversions in solid phase organic synthesis applications has been noted. See Akhtar, et al., Tetrahedron Lett. 2000, 41, 4487; Liu, et al., Tetrahedron Lett. 2000, 41, 4493. Such limitations include the inability to be wetted or swollen by most aprotic organic solvents. Thus, although NAFION™ is robust and chemically resilient, it is not useful in solid-phase organic synthesis because the perfluoropolymer side chains are not solvated. As a result, there is a need in the art for a polymer-supported perfluorosulfonate that is swellable and wettable by most common solvents.
In addition to being used for solid phase organic synthesis, solid and semi-solid supports are also used in solution phase organic chemistry as catalysts or reagents. For example, in the field of catalysis and organic chemistry, there is widespread use of highly acidic catalysts to promote chemical transformations. These often take the form of polymer supported acids, which can be readily filtered away from a reaction mixture at the completion of the reaction. Resins known to those skilled in the art include polystyrene-based resins, controlled pore glass beads, NAFION™, polyethylene glycol resins, TENTAGEL™ (Rapp Polymere GmbH, Tubingen, Germany), and the like. See Olah, Synthesis 1986, 7, 513. Whereas ion-exchange resins, and in particular cation exchange resins, are polymer-supported acids, they are typically based on phenylsulfonic acids and are hence limited in acidity. Perfluorosulfonic acids are dramatically more acidic than phenylsulfonic acids and as such, are quite distinct and often capable of catalyzing a broader range of chemical transformations. Thus, there is a general need in the art for polymer-supported perfluorosulfonic acids and related derivatives.
Processes for making perfluorosulfonic solid acids via encapsulation of perfluorosulfonic acids into hydrocarbon resins have been disclosed in WO 98/30521, however, these are not expected to find application in the field of solid phase organic synthesis because the perfluorosulfonate groups are not covalently bound to the resin.
NAFION™ has been demonstrated to act as a highly acidic supported catalyst. Its properties have been noted by Olah, Synthesis 1986, 7, 513; Yamoto, Recent Res. Devel. In Pure & Applied Chem. 1998, 2, 297; Harmer, Adv. Mater. 1998, 10, 1255. However, NAFION™ and related polymers in the art are not effectively swollen by most aprotic organic solvents. Because NAFION™ is not swellable or wettable by most common organic solvents, only the acid groups on the surface of NAFION™ are available for reaction, while the majority of the acid groups contained within the polymer are unavailable for reaction. One technique of increasing the effective surface area is to grind the polymer into fine particles and to imbed these into an inert carrier such as clay or amorphous silica. See Harmer, Adv. Mater. 1998, 10, 1255. These hybrid materials are subject to leaching artifacts and can often be difficult to filter away due to the heterogeneity of the particles. Thus, there is a need in the art for supported superacids that are swollen by common organic solvents, allowing supported superacids to be used for more applications and under milder reaction conditions. See Ishihara, et al., Angew. Chem. Int. Ed. 2001, 40.
A superacid polymer-supported resin that is swellable would be highly desirable due to the ease of use, the enhanced effective acid content (because most or all of the contained acid groups would be available for use), and compatibility with a wide range of solvents.